Phosphorylation of proteins during response of cells to treatment with phorbol esters (PMA) was studied. In HL-60 promyelocytic leukemia cells, growth arrest and differentiation after PMA exposure are associated with rapid phosphorylation-dephosphorylation of proteins pp17 and pp27. Cell-free studies suggest that this may involve the activation and cooperation of two classes of protein kinase, calcium-phospholipid-dependent kinase and cAMP-dependent kinase. Significantly, enhanced phosphorylation of pp17 and pp27 was found only in cell lines where PMA caused growth arrest and differentiation. The effect was minimal in cells where PMA was mitogenic. PMA also induces aggregation of platelets, during which increased protein phosphorylation occurs. Elevated phosphorylation of class-I HLA molecules was documented, together with evidence suggesting association of HLA in a complex with myosin and actin and implicating modification of HLA as a component of platelet activation.